Colorectal cancer is the third most incident
cancer in the United States and is second only to
lung cancer as a cause of
cancer-related mortality.
Colorectal cancer develops through a multistep process characterized by histopathological precursor lesions and molecular genetic alterations. This sequential process of
tumorigenesis provides opportunities for the development and testing of both primary and
secondary prevention strategies. This review focuses on
chemoprevention, which is defined as the use of natural or synthetic agents to reverse the process of
carcinogenesis. Epidemiological studies have consistently shown that chronic intake of nonsteroidal anti-inflammatory drugs (
NSAIDs), principally
aspirin, can reduce the incidence of colorectal
adenomas and
carcinomas. Evaluation of
NSAIDs, including newer selective cyclo-oxygenase-2 inhibitors, in
carcinogen-induced and genetically manipulated animal models of
colorectal cancer demonstrates that these drugs are effective chemopreventive agents. In humans, the
NSAID sulindac has been studied in
familial adenomatous polyposis patients and was found to regress colorectal
adenomas in a placebo-controlled trial. More recently, the selective cyclo-oxygenase-2 inhibitor
Celebrex was also shown to be effective in
familial adenomatous polyposis and was approved by the Food and Drug Administration as a adjuct to usual care in these patients.
NSAIDs, as well as other chemopreventive agents, are currently being studied in patients at increased risk of
colorectal cancer, including those with sporadic
adenomas. The outcome of these studies has the potential to impact patient management practices. However, chemopreventive agents cannot be recommeded at present for average-risk individuals or for those with sporadic colorectal
neoplasia. In addition to demonstrating efficacy, chemopreventive agents must be safe and well tolerated for chronic administration and should be relatively cost-effective. Although still in its infancy, the field of
chemoprevention is an exciting and rapidly advancing area of investigation. Chemopreventive strategies, if effective, offer the promise of producing a paradigm shift in our current approach to
colorectal cancer.